This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In order to support the required flexibility and future extensibility of our generalized PSE architecture, an additional physical modeling layer will be introduced. The current Virtual Cell features a direct transformation from a domain-specific quantitative process description (the physiological model consisting of chemical, electrophysiological, and transport mechanisms) and user specified assumptions directly to a purely mathematical model. Implicit in this transformation from biological processes to mathematics are the choice of specific physical approximations, geometric mappings, time scales, and the underlying physical laws. The addition of additional modeling domains as well as explicit models of measurement devices (e.g. virtual experiments) call out for an intermediate physical layer where all processes (and equations) are explicit, but still map one-to-one with the process descriptions. The translation from interconnected "physical devices" to solvable systems of equations is then isolated from the formulation of a physically consistent model. Embedded in this layer are the semantics of physical consistency along with those of mathematical consistency. We will define the semantics and operations of this physical layer and provide a reference implementation (allowing for alternate representations such as CellML and Modelica). The specification of this layer provides room for specialized and sophisticated mathematical transformations to transform the physical/mathematical systems into a solvable form.